The oral mucosa provides a protective lining for the oral cavity, limiting the entry of microorganisms, and toxins and antigens. This function is carried out by a superficial intercellular permeability barrier, composed largely of lipid, that limits penetration of water soluble substances. Different regions of the oral cavity show different permeabilities. This has been associated with the frequency of certain oral disease, including premalignant and malignant lesions, the etiology of which may involve the penetration of substances such as alcohol and tobacco components from the mucosal surface. Many of these lesions are more common in the elderly, which raises the question of how barrier function changes with age. The proposed research will examine the putative origin of the barrier components from membrane-coating granules in keratinized and nonkeratinized oral epithelia. It will then examine composition and function, as determined by lipid analysis and permeability measurements, in different regions of human oral mucosa from individuals of different ages. Finally, it will examine the effects of chronic alcohol ingestion on the lipid content, composition and permeability to a tobacco carcinogen (nitrosonornicotine) of oral mucosa in an animal model. The techniques to be used will include tissue fractionation, lipid extraction, thin layer chromatographic analysis and structural characterization and permeability measurements in vitro. Tissues will be obtained from pig and from human autopsies. Rats will be used as an animal model. This represents the first study to attempt to characterize the origin of the barrier in oral epithelium and to examine the effects of age on the structure and function of the barrier in human tissue. It will also seek explanations for the known synergy between alcohol and tobacco in the etiology of oral cancer. Such studies are important in view of the possible role of the permeability barrier in the etiology of a variety of oral mucosal lesions and because of the increased susceptibility of the elderly to such lesions. Answers to the questions posed will facilitate therapy and may lead to preventive strategies.